Transdermal system having a backing layer and a ring system

Abstract

The invention relates to a system comprising: a transdermal therapeutic system (TTS); a cylindrical separating layer having an outer periphery and an inner periphery; and a backing layer, which is applied to the cylindrical separating layer and protrudes beyond the cylindrical separating layer over the entire periphery. The invention further relates to a system for improving the adhesion of a TTS, to the use of said system, and to a kit containing said system.

Description

[0001] The present invention relates to a transdermal system for use in clinical and preclinical studies, the use of a cylindrical separating layer in these studies, and a method for determining pharmacological and physical data. Furthermore, the present invention relates to a system for improving the adhesion of a transdermal therapeutic system (TTS), the use of this system, and a kit containing this system.

[0002] For the development of new transdermal therapeutic systems (TTS), they must be investigated in preclinical and clinical studies. Problems arise during preclinical and clinical studies when the applied drug-containing TTS adheres poorly or only incompletely to the skin. The applied TTS are complete transdermal therapeutic systems, but the adhesive elements may not yet have been optimized. Furthermore, initial studies are usually conducted on minipigs. The texture of minipig skin is very similar to human skin, but the adhesive strength of a TTS is compromised by the minipigs' bristles. Furthermore, the strong mechanical stress in studies with minipigs poses a challenge to the adhesive strength of a TTS.Therefore, the transdermal therapeutic systems are not optimized for adhesion to the skin of minipigs. In the worst case, with prolonged application times and / or difficult application sites and / or mechanical stress, the TTS can completely detach from the skin and fall off.

[0003] Even with commercially available TTS systems, there is an increased risk of premature detachment of the TTS from the human skin, for example due to long periods of wear.

[0004] To prevent premature detachment, the use of an over-plaster is described for systems that lack sufficient adhesion, for example, in DE 102009022915 A1. Such an over-plaster improves the adhesion of the TTS to the skin and protects the TTS from mechanical stress.

[0005] When using such over-patches, the problem often arises that the transdermal therapeutic system (TTS) and the over-patch can no longer be separated after application. In preclinical and clinical studies, it is necessary for the TTS to be analytically evaluated after application. The over-patch interferes with this analytical evaluation or even makes it impossible. Furthermore, there is a risk that the active ingredient from the TTS will migrate over the edges of the TTS's backing into the adhesive layer of the over-patch.

[0006] The object of the present invention was to provide a system in which there is no premature detachment of the TTS and in which there is no migration of the active ingredient over the edges of the back cover belonging to the TTS into the over-plaster.

[0007] This task is solved by a system that includes: (i) a transdermal therapeutic system (TTS) having a side facing the skin and a side facing away from the skin; (ii) a cylindrical separating layer having an outer circumference, an inner circumference, an end face and a bottom face, wherein the cylindrical separating layer is applied to the side of the TTS facing away from the skin and the outer circumference of the cylindrical separating layer completely projects beyond the TTS and the TTS completely projects beyond the inner circumference of the cylindrical separating layer; (iii) an over-patch applied to the cylindrical separating layer and completely projects beyond it.

[0008] According to the invention, the outer circumference of the cylindrical separation layer completely extends beyond the TTS, and the TTS completely extends beyond the inner circumference of the cylindrical separation layer. This means that the TTS and the cylindrical separation layer overlap. The TTS is a flat system with an outer circumference that is larger than the inner circumference of the cylindrical separation layer, but smaller than the outer circumference of the cylindrical separation layer. Because the outer circumference of the cylindrical separation layer is larger than the outer circumference of the TTS, the cylindrical separation layer overlaps the edges of the rear cover belonging to the TTS. This prevents the edges of the TTS from coming into contact with the overlay.

[0009] To prevent migration of the active ingredient over the edges of the backing layer belonging to the TTS into the over-plaster, it is preferred that the cylindrical separating layer is impermeable to the active ingredient.

[0010] There are no specific limitations regarding the size of the inner circumference of the cylindrical separating layer, provided the inner circumference of the cylindrical separating layer is smaller than the outer circumference of the TTS, so that the TTS completely extends beyond the inner circumference of the cylindrical separating layer. The inner circumference of the separating layer encloses an area whose surface area is preferably from 0.1 to 30.0 cm², particularly preferably from 1.0 to 15.0 cm², and most preferably from 5.0 to 10.0 cm².

[0011] Because the cylindrical separating layer has an inner perimeter, the overlay can contact the TTS within the area formed by the inner perimeter of the cylindrical separating layer. When the overlay and the TTS come into contact via the area formed by the inner perimeter of the cylindrical separating layer, the TTS adheres to the overlay. This allows for better fixation of the TTS, preventing it from slipping under the overlay.

[0012] Furthermore, the cylindrical separating layer preferably has a thickness of 5 to 20 µm, particularly preferably 8 to 17 µm, most preferably 10 to 15 µm.

[0013] There are no specific limitations regarding the area in which the TTS extends beyond the inner circumference of the cylindrical separating layer. Preferably, the TTS extends beyond the inner circumference of the cylindrical separating layer by at least 1 mm, particularly preferably at least 3 mm, and most preferably at least 5 mm.

[0014] Furthermore, it is preferred that the outer circumference of the cylindrical separating layer completely projects beyond the TTS by at least 1 mm, particularly preferably at least 3 mm, most preferably at least 5 mm.

[0015] There are no specific limitations regarding the shape of the cylindrical separating layer, provided that the cylindrical separating layer has an outer circumference, an inner circumference, an end face, and a bottom face. The outer circumference and inner circumference of the cylindrical separating layer independently have a circular, oval, or polygonal shape. If the separating layer has a polygonal shape, it is preferable that the corners be rounded.

[0016] The outer circumference and the inner circumference can have an identical or different shape. Preferably, the outer circumference and the inner circumference have an identical shape. Particularly preferably, the outer circumference and the inner circumference of the cylindrical separating layer have a round or oval shape. It is preferred that the outer circumference of the separating layer corresponds to the outer shape of the TTS used, and the outer shape of the separating layer projects beyond the outer shape of the TTS. Figure 1shows a view of the system according to the invention from below, i.e. from the skin side. Figure 2 shows a side view of the system according to the invention.

[0017] The system according to the invention comprises a TTS (1), a foil ring (2) and an over-plaster (3), wherein the foil ring represents the cylindrical separating layer.

[0018] There are no specific limitations regarding the material from which the cylindrical separating layer is constructed. The cylindrical separating layer can be adhesive or non-adhesive. Preferably, the cylindrical separating layer consists of a material selected from the group consisting of polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymers, nylon, ethylene-vinyl acetate copolymers, plasticized polyvinyl chloride, polyurethane, polyvinylidene chloride, polypropylene, polyethylene, or polyamide.

[0019] The over-plaster is preferably made of a textile fabric. The fabric can be elastic in one or two directions. To ensure secure attachment to the skin and the actual TTS, the over-plaster is equipped with an adhesive layer.

[0020] Suitable base polymers for a pressure-sensitive adhesive layer are described, for example, in Tan, Pfister, PSTT Vol. 2, No. 2, February 1999, pages 60-69. Suitable base polymers include polyacrylates, poly(meth)acrylates, polyacrylic acid, cellulose derivatives, especially methyl and ethyl celluloses, polyisobutylene, ethylene-vinyl acetate copolymers, natural and synthetic rubbers such as styrene-diene copolymers, styrene-butadiene block copolymers, styrene-isoprene block copolymers, acrylonitrile-butadiene rubber, butyl rubber, or neoprene rubber, as well as hot-melt adhesives. Silicone-based pressure-sensitive adhesives can also be considered. Suitable mixtures of the aforementioned polymers or hybrid adhesives made of acrylate monomers and silicone monomers can also be used advantageously.

[0021] According to the invention, the pressure-sensitive adhesive layer with which the over-plaster is provided contains, as base polymers, polymers which are preferably selected from the group comprising polyacrylates, poly(meth)acrylates, polyacrylic acid, cellulose derivatives, polyisobutylene, ethylene-vinyl acetate copolymers, natural and synthetic rubbers such as styrene-diene copolymers, styrene-butadiene block copolymers, styrene-isoprene block copolymers, acrylonitrile-butadiene rubber, butyl rubber or neoprene rubber, as well as hot-melt adhesives and silicone-based pressure-sensitive adhesives.

[0022] The TTS used in the system according to the invention is a complete TTS that (a) a drug carrier or drug reservoir and (b) a backing layer.

[0023] The backing layer of a TTS must be impermeable to the active ingredient contained in the TTS to prevent unwanted leakage of the active ingredient from the side of the TTS facing away from the skin. Special plastic films, such as metallized plastic films, are used for this purpose. Aluminized films made of polyethylene terephthalate are preferred. The advantage of using a metallized film is that it is impermeable to almost all pharmaceutical active ingredients and light, which offers the advantage of reliable light protection, especially for light-sensitive active ingredients.

[0024] Polyesters characterized by their exceptional strength, such as polyethylene terephthalate and polybutylene terephthalate, are particularly suitable materials for the drug-impermeable backing layer of the TTS. However, virtually any other skin-compatible plastics, such as polyvinyl chloride, polyurethane, polyvinylidene chloride, ethylene-vinyl acetate copolymers, polyvinyl acetate, vinyl acetate-vinyl chloride copolymers, nylon, polyethylene, polypropylene, polyurethanes, polyamide, cellulose derivatives, and many others, are also suitable. Polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymers, nylon, ethylene-vinyl acetate copolymers, plasticized polyvinyl chloride, polyurethane, polyvinylidene chloride, polypropylene, polyethylene, and polyamide are preferred.

[0025] In the system according to the invention, the cylindrical separating layer is applied to the backing layer of the TTS.

[0026] If the system according to the invention is to be analytically evaluated after application, the cylindrical separating layer is preferably non-adhesive. Such a system according to the invention is characterized in that the TTS, the cylindrical separating layer, and the over-plaster are separable from one another. This facilitates analytical evaluation after application, since the analytical data are not distorted by the presence of the over-plaster.

[0027] Furthermore, the present invention relates to the use of a non-adhesive, cylindrical separating layer having an outer circumference, an inner circumference, an end face and a bottom face for determining pharmacological and physical data in clinical and preclinical studies.

[0028] The present invention further relates to a method for determining pharmacological and physical data comprising: (a) Providing a system according to the invention comprising: (a1) applying a non-adhesive, cylindrical release layer having an outer circumference, an inner circumference, an end face and a bottom face to a TTS with a side facing the skin and a side facing away from the skin, such that the non-adhesive, cylindrical release layer is applied to the side of the TTS facing away from the skin and the outer circumference of the non-adhesive, cylindrical release layer completely projects beyond the TTS and the TTS completely projects beyond the inner circumference of the non-adhesive, cylindrical release layer; (a2) applying an over-plaster to the non-adhesive, cylindrical release layer such that the over-plaster completely projects beyond the non-adhesive, cylindrical release layer; (b) applying the system obtained from (a) to skin; (c) collecting pharmacological and physical data.

[0029] Furthermore, the present invention relates to a system for improving the adhesion of a TTS comprising: (ii) a cylindrical separating layer having an outer perimeter, an inner perimeter, an end face, and a bottom face; (iii) an overlay applied to and extending entirely beyond the cylindrical separating layer.

[0030] The cylindrical separating layer (ii) and the over-plaster (iii) are as previously described.

[0031] The present invention also relates to the use of a system comprising: (ii) a cylindrical separating layer having an outer perimeter, an inner perimeter, an end face, and a bottom face; (iii) an overlay applied to and extending entirely beyond the cylindrical separating layer; to improve the adhesion of a TTS and / or to prevent migration of the active ingredient over the edges of the TTS.

[0032] Such a system is used together with a commercially available TTS, whereby the cylindrical separating layer is applied to the side of the TTS facing away from the skin and the outer circumference of the cylindrical separating layer completely extends beyond the TTS and the TTS completely extends beyond the inner circumference of the cylindrical separating layer.

[0033] There are no specific restrictions regarding the active ingredient used in the TTS, provided the active ingredient is suitable for administration via a TTS. An example of such an active ingredient is buprenorphine. Examples of commercially available buprenorphine-containing TTSs are Transtec ®< , Norspan ®< , and Butrans ®< .

[0034] As already explained, the over-patch contacts the TTS within the area formed by the inner perimeter of the cylindrical separating layer, and the TTS adheres to the over-patch. This makes it possible to fix a commercially available TTS and thus improve its adhesion to the skin. Furthermore, with such a system, no migration of the active ingredient beyond the edges of the TTS occurs, as the outer perimeter of the cylindrical separating layer completely extends beyond the TTS.

[0035] Furthermore, the present invention relates to a kit comprising: a transdermal therapeutic system (TTS) and a system according to the invention for improving the adhesion of a TTS comprising: (ii) a cylindrical separating layer having an outer perimeter, an inner perimeter, an end face, and a bottom face; (iii) an overlay applied to and extending entirely beyond the cylindrical separating layer.

Claims

1. System comprising: (i) a transdermal therapeutic system (TTS) with a side facing towards the skin and a side facing away from the skin; (ii) a cylindrical release layer with an outer circumference, an inner circumference, a front face and a bottom face, wherein the cylindrical release layer is applied to the side of the TTS facing away from the skin, and the outer circumference of the cylindrical release layer protrudes fully circumferentially over the TTS, and the TTS protrudes fully circumferentially over the inner circumference of the cylindrical release layer; (iii) an overplaster which is applied to the cylindrical release layer and protrudes fully circumferentially over the latter, the cylindrical release layer being impermeable to active substance, and the overplaster being equipped with a pressure-sensitive adhesive layer for fixing to the skin.

2. System according to Claim 1, characterized in that the inner circumference of the cylindrical release layer encloses an area whose area content is from 0.1 to 30.0 cm2, preferably from 1.0 to 15.0 cm2, particularly preferably from 5.0 to 10.0 cm2, and the cylindrical release layer has a thickness of 5 to 20 µm,preferably of 8 to 17 µm, particularly preferably of 10 to 15 µm.

3. System according to Claim 1 or 2, characterized in that the TTS protrudes fully circumferentially over the inner circumference of the cylindrical release layer by at least 1 mm, preferably by at least 3 mm, particularly preferably by at least 5 mm, and the outer circumference of the cylindrical release layer protrudes fully circumferentially over the TTS by at least 1 mm, preferably by at least 3 mm, particularly preferably by at least 5 mm, and wherein the outer circumference and the inner circumference of the cylindrical release layer have, independently of each other, a circular, oval or polygonal shape.

4. System according to one or more of Claims 1 to 3, characterized in that the cylindrical release layer is made of a material selected from the group comprising polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymers, nylon, ethylene-vinyl acetate copolymers, plasticized polyvinyl chloride, polyurethane, polyvinylidene chloride, polypropylene, polyethylene or polyamide.

5. System according to one or more of Claims 1 to 4, characterized in that the pressure-sensitive adhesive layer contains, as base polymer, polymers preferably selected from the group comprising polyacrylates, poly(meth)acrylates, polyacrylic acid, cellulose derivatives, polyisobutylene, ethylene-vinyl acetate copolymers, natural and synthetic rubbers such as styrene-diene copolymers, styrene-butadiene block copolymers, styrene-isoprene block copolymers, acrylonitrile butadiene rubber, butyl rubber or neoprene rubber, and also hot-melt adhesives and pressure-sensitive adhesives based on silicone.

6. System according to one or more of Claims 1 to 5, characterized in that the TTS comprises (a) an active substance carrier or an active substance reservoir and (b) a backing layer.

7. System according to Claim 6, characterized in that the cylindrical release layer is applied to the backing layer of the TTS.

8. System according to one or more of Claims 1 to 7, characterized in that the cylindrical release layer is not adhesive, and the TTS, the cylindrical release layer and the overplaster are separable from one another.

9. Method for the determination of pharmacological and physical data, comprising: (a) making available a system according to one or more of Claims 1 to 8, wherein the release layer is a non-adhesive, cylindrical release layer, comprising: (a1) applying a non-adhesive, cylindrical release layer with an outer circumference, an inner circumference, a front face and a bottom face to a TTS with a side facing towards the skin and a side facing away from the skin, such that the non-adhesive, cylindrical release layer is applied to the side of the TTS facing away from the skin, and the outer circumference of the non-adhesive, cylindrical release layer protrudes fully circumferentially over the TTS, and the TTS protrudes fully circumferentially over the inner circumference of the non-adhesive, cylindrical release layer; (a2) applying an overplaster to the non-adhesive, cylindrical release layer, such that the overplaster protrudes fully circumferentially over the non-adhesive, cylindrical release layer; (b) applying the system obtained from (a) to skin; (c) collecting pharmacological and physical data.

10. System for improving the adhesion of a TTS, comprising: (ii) a cylindrical release layer with an outer circumference, an inner circumference, a front face and a bottom face; (iii) an overplaster which is applied to the cylindrical release layer and protrudes fully circumferentially over the latter.

11. Kit comprising: a transdermal therapeutic system (TTS) and a system according to Claim 10.

12. Use of a system according to Claim 10 for improving the adhesion of a TTS and / or for preventing the migration of the active substance over the edges of the TTS.

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